MILK

1. MILK Hala Mosli PGY-5 November 4, 2009

2. Objectives: • What is prolactin? • Where does it come from? • How is it regulated? • Disorders of prolactin production.

3. Prolactin • 198-Amino acid polypeptide hormone. • Contains three intra-molecular disulfide bonds. • Gene located on chromosome 6. • Circulates in the blood in different sizes: • Monomeric PRL (little PRL; 23 kd) • Dimeric PRL (big PRL; 48-56 kd) • Polymeric PRL (Big big PRL; >100 kd)

4. Shares a common tertiary structure with a family of polypeptide hormones, eg GH and HPL and are structurally related to members of the cytokine-hematopoietin family (EPO, GM-CSF, IL-2-IL-7). • Biological effects produced by interacting with and dimerizing specific single transmembrane-domain receptors. • The receptors belong to a superfamily of cytokine receptors.

6. Synthesized and secreted from the lactotrophs of the anterior pituitary gland. • A precursor molecule (MW 40,000-50,000) is also secreted and may constitute 8-20% of prolactin immunoreactivity.

7. Regulation • Hypothalamic control of PRL secretion is mainly inhibitory. • Dopamine is the most important inhibitory factor.

9. Many factors influence PRL secretion: • Physiologic • Pharmacologic • Pathologic

13. Lactotroph cells • Make up 15-25% of functioning anterior pituitary cells. • Absolute number does not change with age. • Hyperplasia occurs during pregnancy and lactation.

14. Most PRL-expressing cells appear to arise from GH-producing cells. • Two cell forms express PRL gene: • Large polyhedral cells throughout the gland contain large secretory granules. • Smaller, angulated or elongated cells clustered mainly in the lateral wings and median wedge sparse smaller granules. • Occasional mammosomatotrophs cosecrete both GH and PRL, often stored within the same granules.

16. Functions • Mammary gland development and lactation: • Puberty: PRL is not essential for pubertal mammary gland development. • Pregnancy: PRL increases to a mean of 207 μg/L. Amniotic fluid PRL is 100 times that level. • Plays a role in mammary gland maturation in the third trimester of gestation.

17. Lactation: active lactation is due in part to a fall in estrogen and progesterone and an elevation of PRL after delivery. • Suckling is essential to maintain lactation. • Without suckling, prolactin levels fall to normal within 7 days post-partum. • As nursing continues, PRL concentrations fall.

18. Each suckling episode causes an episodic rise in PRL. • Milk yield does not closely correlate with serum PRL level. • Suckling also stimulates oxytocin release from the posterior pituitary. • Oxytocin induces milk ejection by stimulating the contraction of myoepithelial cells, as well having important effects on alveolar proliferation.

19. Immune function: • PRL is a lymphocyte growth factor. • It also stimulates immune responsiveness. • PRL levels change in patients with Lupus and other immune disease. • Exact role in immunomodulation is not clear.

20. Reproductive/ gonadal function: • PRL has no physiologic role in the regulation of gonadal function. • Hyperprolactinemia leads to hypogonadism. • Exact mechanisms unknown but likely due to alteration of the hypothalamic-pituitary control of gonadotrophin secretion.

21. In women: • Shortened luteal phase. • Normal basal LH and FSH normal but pulsatile secretion is decreased. • This interferes with the midcycle LH surge. • Anovulation, oligomenorrhea, amenorrhea • Infertility • In men: • Decreased testosterone synthesis and decreased spermatogenesis. • Decreased libido and impotence. • Infertility.

22. PROLACTINOMA • Definition: • Prolactinomas are pituitary adenomas that express and secrete prolactin to variable degrees • They are almost invariably benign. • Occasionally, these adenomas can be aggressive or locally invasive and cause compression of vital structures. • Malignant prolactinomas that are resistant to treatment and disseminate inside and outside the central nervous system are very rare

23. Epidemiology • Prolactinomas are the most frequent pituitary tumors, with an estimated prevalence in the adult population of 100 per million population. • Beckers et al. found a much higher prevalence at 55 per 71,000 (775 per million) inhabitants in Belgium.

24. Their frequency varies with age and sex, occurring most frequently in females between 20 and 50 yr old, when the ratio between the sexes is estimated to be 10:1. • After the fifth decade of life, the frequency of prolactinomas is similar in both sexes. • In the pediatric/adolescent age, prolactinomas are rare, but represent about half of all pituitary adenomas, which, overall, account for less than 2% of intracranial tumors

25. Classification • Classified according to size into: • Microadenomas: less than 10 mm in diameter • Macroadenomas: more than 10 mm in diameter • Over 90% of prolactinomas are small, intrasellar tumours that rarely increase in size.

26. Pathogenesis • Multi-step process that involves dysregulation of cell growth or proliferation, differentiation, and hormone production. • It may be initiated as a result of activation of oncogene function or after inactivation of a tumor suppressor gene, or both. • Studies have demonstrated that pituitary tumors are monoclonal in origin thus tumors arise from a single cell mutation followed by clonal expansion.

27. Manifestations • Related to excess hormone production: hyperprolactinemia. • Mechanical symptoms. • Symptoms of impaired pituitary function.

28. Excess hormone production: • Galactorrhea-amenorrhea • Infertility • Decreased libido/ impotence.

29. Galactorrhea-amenorrhea syndromes: • Three distinct clinical syndromes described: 1) the Chiari-Frommel Syndrome—amenorrhea, galactorrhea, and low urinary gonadotropins occurring postpartum 2) Ahumada-Argonz-del Castillo syndrome—nonpuerperal amenorrhea, galactorrhea, and low urinary gonadotropins with no evidence of a pituitary tumor on standard skull x-rays 3) Forbes-Henneman-Griswold-Albright syndrome—nonpuerperal amenorrhea, galactorrhea, and low urinary gonadotropins in association with a chromophobe adenoma

30. Other symptoms: • Weight gain, fluid retention. • Hirsutism • Irritibality, anxiety and depression,

31. Mechanical symptoms: • Headaches: • A study was conducted by Strebel et al, to determine whether headaches in women with non-puerperal hyperprolactinemia were associated with hyperprolactinemia or the presence of a prolactinoma. • Headaches were found to be four times more common in the presence of a prolactinoma than in its absence.

33. Visual field defects: • Disorders of the visual fields have been documented in the literature in association with pituitary gland tumors since the early 1900’s. • Types of bitemporal defects are stages in a progressive restriction of the visual fields. The fielddefect usually begins in the upper temporal quadrant and progresses into a bitemporal hemianopia. This may advance to involve the nasal aspects of the visual fields as well.

34. Cranial Nerve Palsies: • Not a frequent manifestation. • Pituitary adenomata tend to displace or encircle the cranial nerves rather than invade them. • Seen in more aggressive, invasive tumors that extend into the cavernous sinus.

35. Cavernous Sinus Invasion by Pituitary Adenomas, Ahmadi et al AJR 146:257-262, February 1986

36. Impairment of Pituitary Function: • Due to compression of normal pituitary tissue. • Manifests as partial or panhypopituitarism. • Almost always seen in macroadenomas.

37. Lab Evaluation • Normal prolactin levels in women and men are below 25 μg/l and 20 μg/l, respectively, with the more commonly used assays (1μg/l is equivalent to 21.2 mIU/l) • PRL values between the upper limits of normal and 100 μg/l (∼2000 mIU/l) may be due to psychoactive drugs, estrogen, or functional (idiopathic) causes, but can also be caused by microprolactinomas.

38. Most patients with PRL levels over 150 μg/l (∼3000 mIU/l) (five times higher than the normal values) will have a prolactinoma. • Macroadenomas are typically associated with levels of over 250μg/l (∼5000 mIU/l),and in some cases over 1000μg/l (∼20000 mIU/l) • Such values are not absolute; prolactinomas can present with variable elevations in PRL, and there may be dissociation between tumour mass and hormonal secretion.

39. There are two potential pitfalls in the diagnosis of a prolactinoma: • Macroprolactin • Hook effect

40. Macroprolactin is a complex of PRL and an IgG antibody. • Serum PRL concentrations are elevated secondary to a reduced rate of clearance of this complex. • Macroprolactin has reduced bioactivity and is present in significant amounts in up to 20% of hyperprolactinemic sera, resulting in pseudo-hyperprolactinaemia and potential misdiagnosis. • Macroprolactin is detected by most but not all PRL assays; therefore each centre must know the specific characteristics of the prolactin immunoassay they use.

41. The ‘hook effect’ may be observed when the serum PRL concentration is extremely high, as in some cases of giant prolactinomas. • The high amount of circulating PRL causes antibody saturation in the immunoradiometric assay, leading to artifactually low results. • To overcome the hook effect, an immunoradiometric PRL assay should be performed at a serum dilution at 1 : 100, or alternatively should include a washout between the binding to the first antigen and the second step in order to eliminate excess unbound PRL. • It has been recommended that the hook effect be excluded in all new patients with large pituitary macroadenomas who have normal or mildly elevated PRL levels.

42. Dynamic tests of prolactin secretion: • Several dynamic tests of PRL secretion have been proposed as diagnostic tools in the evaluation of hyperprolactinaemia, • These include the administration of TRH,L-dopa, nomifensine, domperidone, and insulin-induced hypoglycaemia. • Despite the fact that some of these methods are useful in particular hands it is now widely accepted that the diagnosis of a prolactinoma should be confirmed by analysing basal PRL values, imaging the pituitary, and excluding other causes.

43. IMAGING: • Gadolinium-enhanced MRI is the study of choice. • Computed tomography (CT) with intravenous contrast enhancement is less effective than MRI in diagnosing small adenomas and in defining the extension of large tumours, but may be used if MRI is unavailable or contraindicated. • However, microadenomas are present in about 10% of the normal population. • Normal MRI examination does not necessarily exclude a microadenoma.

45. Patients with macroadenomas that abut the optic chiasm should undergo formal visual-field examination. • Hyperprolactinaemia in the presence of an MRI-detected pituitary adenoma is consistent with but not unequivocally diagnostic of a prolactinoma, because any pituitary mass that compresses the pituitary stalk may cause hyperprolactinaemia. • Unequivocal diagnosis requires pathological analysis, but prolactinomas are rarely surgically removed.

47. Therapy • Medical • Surgical • Radiation

49. Medical Management • Mainstay of management are dopamine agonists. • Dopamine inhibition of PRL secretion is mediated by the D2 dopamine receptors expressed by normal and tumorous lactotrophs • The inhibition of cAMP levels is a key step in the inhibition of PRL release by dopamine and it is likely that all dopaminergic ergot derivative share similar mechanisms of action.

50. Dopamine agonists reduce the size of prolactinomas by inducing a reduction in cell volume • This is via an early inhibition of secretory mechanism, and a late inhibition of gene transcription and PRL synthesis • They also cause perivascular fibrosis and partial cell necrosis. • There may also be a true antimitotic effect of these drugs. • Histologically, there is a reduction in secretory activity and cell size, an increase in immunoreactive PRL cellular content and inhibition of exocytosis